Specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference in colon cancer cells

Xia,

doi:10.3892/or_00000163

Cited by 17 publications

(21 citation statements)

References 3 publications

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“…The downregulation of Wip1 gene expression could enhance the chemosensitivity of RKO colon cancer cells, which provided a new potential approach for the reversal of multidrug resistance in colon cancer. However, siRNA transient transfection has certain disadvantages such unsatisfactory inhibition of the target gene and short time effects (5). Furthermore, the results of the present study were obtained in vitro.…”

Section: Ic 50 (µMol/l Mean ± Standard Deviation) ------------------supporting

confidence: 53%

“…In previous studies, calcium antagonists such as verapamil (4) and small interfering RNA (siRNA) targeting multidrug resistance protein 1 (MDR1) messenger RNA (mRNA) were observed to modulate MDR1/P-glycoprotein (P-gp)-dependent MDR by downregulating the expression of MDR1 mRNA and P-gp (5). However, calcium antagonists may cause heart failure and hypotension (6), and the clinical benefit of siRNA targeting MDR1 mRNA has not been reported thus far.…”

Section: Introductionmentioning

confidence: 99%

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Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Xia

et al. 2017

Oncology Letters

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Abstract. Colon cancer is one of the most common cancers in the world. Multidrug resistance is one of the main reasons for failure of therapy in patients with advanced colon cancer. In previous studies, multiple methods were investigated to reverse the multidrug resistance of colon cancer cells. However, to date, no clinical method has been identified to be satisfactory. Therefore, successful reversal of drug resistance in colon cancer cells still requires new therapeutic strategies or pharmaceuticals. Wild-type p53-induced phosphatase (Wip1), a member of the 2C type serine/threonine protein phosphatase family, is closely associated with the p53 gene, which is the most important tumor-suppressor gene. Wip1 was reported to be associated with the chemosensitivity of breast cancer cells. However, the correlation between the expression of Wip1 gene and the chemosensitivity of colon cancer cells has not been reported yet. In the present study, Wip1-811 small interfering RNA (siRNA) targeting Wip1 was investigated to reverse the multidrug resistance of colon cancer cells. The siRNA duplexes were transfected into RKO colon cancer cells. The messenger RNA (mRNA) expression of Wip1 was measured by reverse transcription-quantitative polymerase chain reaction. The protein level of Wip1 was detected by western blotting. The cell viability was measured by MTS assay. The cell apoptosis and cell cycle were analyzed by flow cytometry. Intracellular adriamycin cumulative concentration was determined using flow cytometry. Wip1-811 siRNA efficiently inhibited the expression of Wip1 at the mRNA and protein levels, and enhanced the sensitivity of RKO colon cancer cells towards chemotherapy, which was accompanied by increased cell apoptosis, following the inhibition of Wip1 gene expression. These results indicate that Wip1 gene silencing could enhance the chemosensitivity of colon cancer cells, which may provide a new potential approach for the reversal of multidrug resistance in colon cancer cells.

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Section: Ic 50 (µMol/l Mean ± Standard Deviation) ------------------supporting

confidence: 53%

Section: Introductionmentioning

confidence: 99%

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Xia

et al. 2017

Oncology Letters

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“…Although the debate about the clinical relevance of efflux-mediated drug resistance is currently ongoing, HCT-15 and COLO320DM cells express MDR1 and are resistant to several chemotherapy drugs (18)(19)(20). A number of chemotherapy-resistant cell lines have been developed using K562 leukemia cells (21)(22)(23).…”

Section: Discussionmentioning

confidence: 99%

TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

Hikichi

Honda

Hikami

et al. 2012

Molecular Cancer Therapeutics

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Polo-like kinase 1 (PLK1) is a serine/threonine protein kinase involved in key processes during mitosis. Human PLK1 has been shown to be overexpressed in various human cancers, and elevated levels of PLK1 have been associated with poor prognosis, making it an attractive target for anticancer therapy. 7,8,is a novel, investigational, orally bioavailable, potent, and selective PLK1 inhibitor that has shown activity in several tumor cell lines, including those that express multidrug-resistant protein 1 (MDR1). Consistent with PLK1 inhibition, TAK-960 treatment caused accumulation of G 2 -M cells, aberrant polo mitosis morphology, and increased phosphorylation of histone H3 (pHH3) in vitro and in vivo. TAK-960 inhibited proliferation of multiple cancer cell lines, with mean EC 50 values ranging from 8.4 to 46.9 nmol/L, but not in nondividing normal cells (EC 50 >1,000 nmol/L). The mutation status of TP53 or KRAS and MDR1 expression did not correlate with the potency of TAK-960 in the cell lines tested. In animal models, oral administration of TAK-960 increased pHH3 in a dose-dependent manner and significantly inhibited the growth of HT-29 colorectal cancer xenografts. Treatment with once daily TAK-960 exhibited significant efficacy against multiple tumor xenografts, including an adriamycin/paclitaxel-resistant xenograft model and a disseminated leukemia model. TAK-960 has entered clinical evaluation in patients with advanced cancers. Mol Cancer Ther; 11(3); 700-9. Ó2011 AACR.

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“…HT-29 does not express P-gp (14), but does exhibit MDR related to the expression of MRP (15). In our previous study (10), the human COLO 320DM colon cancer cell line with HT-29 cells as the control were used to investigate the reversal of MDR1/P-gp-dependent MDR by #4123 and #4029 MDR1 siRNAs targeting MDR1 mRNA. The efficacy of the MDR1 siRNAs in knocking down the phenotype of MDR in COLO 320DM cells, without knocking down MDR effects in the HT-29 control cells, was clearly demonstrated.…”

Section: Discussionmentioning

confidence: 99%

“…In our previous study, siRNAs targeting MDR1 mRNA in colon cancer cells suppressed its expression as well as that of P-gp, reversing the MDR of colon cancer cells (10). However, a major disadvantage of this approach is the transient gene expression-inhibiting effect of chemically synthesized siRNAs.…”

Section: Introductionmentioning

confidence: 99%

Stable reversal of multidrug resistance in colon cancer cells by RNA interference targeting the MDR1 gene

Xia

Zhang

Chen³

et al. 2009

Mol Med Rep

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Abstract. Colon cancer is one of the most common cancers in the world. Overexpression of MDR1 mRNA and P-gp is associated with the classic multidrug resistance of colon cancer cells. In our previous study, we reported on the transient specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference (RNAi) in colon cancer cells. In this study, RNAi targeting the MDR1 gene stably reversed MDR1/P-gp-dependent multidrug resistance in colon cancer cells. The plasmid vectors pSilencer-#4029, encoding #4029 MDR1 siRNA, and pSilencer-#4123, encoding #4123 MDR1 siRNA, were constructed and then transfected into COLO 320DM, a colon cancer multidrug-resistant cell line. Clone cells were screened by G418 and identified by RT-PCR and Western blot analysis. Cellular viability was measured using the MTT assay. Cell cycle analysis and intracellular adriamycin accumulation were assessed by flow cytometry. MDR1 mRNA and P-gp expression in positive clone cells, those stably transfected with MDR1 siRNA, was inhibited. The IC 50 values of the antitumor drugs were significantly decreased in the positive clones compared to the COLO 320DM parent cell line, and the PI/AI values of positive clones treated with antitumor drugs were significantly decreased compared to the parent cells. In addition, the intracellular adriamycin accumulation of positive clones treated with adriamycin was significantly increased compared with COLO 320DM. This demonstrates that the stable transfection of plasmid vectors encoding MDR1 siRNA can stably reverse the MDR1/P-gp-dependent multidrug resistance of colon cancer cells.

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Specific reversal of MDR1/P-gp-dependent multidrug resistance by RNA interference in colon cancer cells

Cited by 17 publications

References 3 publications

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

Wip1 gene silencing enhances the chemosensitivity of human colon cancer cells

TAK-960, a Novel, Orally Available, Selective Inhibitor of Polo-Like Kinase 1, Shows Broad-spectrum Preclinical Antitumor Activity in Multiple Dosing Regimens

Stable reversal of multidrug resistance in colon cancer cells by RNA interference targeting the MDR1 gene

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